Brief Critical Reviews

February 2003: 69 79

Antioxidant Vitamins E and C and Risk of Alzheimers Disease

Age-related neurodegenerative disorders are increasing rapidly. Alzheimers disease is the most common cause of dementia associated with aging. A recent study has examined the role of vitamins E and C in a prospective epidemiologic cohort study and suggested that they might protect against Alzheimers disease. Key Words: antioxidant, Alzheimers disease, neurocognition, aging
2003 International Life Sciences Institute doi: 10.131/nr.2003.febr.69 73

Alzheimers disease (AD) is characterized by regional neuronal degeneration, synaptic loss, and the presence of neurobrillary tangles and senile plaques.1 Neurobrillary tangles are aggregates of hyperphosphorylated microtubular tau protein, whereas senile plaques are complex extracellular lesions composed of a core containing -amyloid (A) surrounded by activated microglia, brillary astrocytes, and dystrophic neurites. AD is the most common cause of dementia in North America and Europe, accounting for one-half to two-thirds of all cases of dementia.2,3 The prevalence of AD varies from approximately 3% in persons aged 65 year to almost 50% in those over 85 years.4,5 AD has the potential to become the most overwhelming public health concern of this century owing to increasing life expectancy and growth in the aging population. The estimated cost of AD is at least $100 billion per year. Based on a recent study by Koppel and the Alzheimers Association in 2002, the projected cost of AD to American businesses will be more than $61 billion, twice the amount calculated just 4 years ago. With a growing elderly population, the cost of AD will increase almost fourfold in the next few decades.6 The report, commissioned by the Alzheimers Association, warns that the cost to U.S. businesses and the nation will continue to soar as baby boomers hit the highest-risk age for developing the disease. The cost of AD is exceeded only by heart disease and cancer. The costs for families, government, and business, if no pre-

This review was prepared by Antonio Martin, M.D., Ph.D., Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
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ventive measurements and new therapies begin soon, will be unsustainable. Thus, recognition of the early symptoms of AD and initiation of even modestly effective interventions to prevent or delay onset are urgently needed to alleviate the growing economic and societal burden associated with AD (Figure 1).7 A decade of research has suggested that reactive oxygen species (ROS) may contribute to the neuronal damage in AD. Some consider oxidative damage to be one of the early markers of neuronal dysfunction in AD. Many support the hypothesis that with advancing age comes increased production of ROS and diminished capacity of the body to protect against ROS, which may consequently lead to an increased oxidizing cellular environment.8,9 In vitro studies have reported a strong correlation between A and generation of free radicals.10 12 Because increased production and deposition of A are early events in the pathogenesis of AD that precede other changes such as the formation of tau, amyloid production and deposition may be associated with increased oxidative stress.13 Hence, the presence of a higher concentration of antioxidants may provide protection to neurons and preserve cognitive function. Other researchers, however, have measured plasma levels of 8-epiPGF2 as a marker of oxidation, and did not detect alterations in oxidative stress with aging or in AD.14 Thus, even though A may cause neuronal toxicity via free radicalinduced insult, other mechanisms are proposed to be involved in the pathogenesis of AD including inammation.15,16 A can activate inammatory pathways by enhancing the microglial secretion of inammatory cytokines such as interleukin (IL)-1 and IL-6. Supporting a possible role of inammation in the pathogenesis of AD, epidemiologic studies strongly suggest that the use of nonsteroidal anti-inammatory drugs (NSAIDs) may reduce the risk of developing AD. Using peripheral levels of C-reactive protein (CRP) as a marker of general inammation, a recent study found that men in the upper three quartiles of plasma CRP had a signicant threefold increased risk for all dementias combined, AD, and vascular dementia, compared with men in the lowest quartile.17 Recent animal studies, using orally administered ibuprofen for 6 months, also lend new experimental support to the theory that NSAIDs may be useful to the
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Figure 1. Environmental agents, such as diet, lifestyle, infection, and education are as important as genetic factors in the etiology of AD. Research indicates that A peptide, which is secreted by neurons, is involved in the pathogenesis of AD. Inammation, produced as a response of the glial cell activation, is a critical component of AD pathology involved in the neurologic damage that results in AD. AD Alzheimers disease, APP amyloid precursor protein.

treatment of AD.18 Therefore, treatment of persons at risk of AD with anti-inammatory drugs or nutrients that affect the inammatory response may be benecial. For example, vitamin E may affect the inammatory response in the central nervous system and at the peripheral level by modulating inammatory components that may be associated with AD. At present, various studies19 24 are seeking to determine whether using vitamin E, a common NSAID drug, or a selective cyclooxygenase-2 (COX-2) inhibitor can help delay the onset of AD in individuals with mild cognitive impairment. Simultaneous administration of vitamin E constitutes a novel approach to down-regulate expression or render COX-2 more sensitive to inhibition by NSAIDs.25
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Vitamin E deciency can cause neurologic dysfunction, but the underlying molecular mechanisms remain unclear. Because of its antioxidant properties, vitamin E (-tocopherol) may play an important role in preventing diseases associated with oxidative stress.26,27 Hence, a benecial effect of vitamin E in reducing the risk of AD could be mediated by an antioxidant effect. However, other novel mechanisms of vitamin E action involving modulation of cellular signaling and transcriptional regulation may be relevant to an understanding of vitamin Es effects on brain function. The role of vitamin E would be signicantly underestimated if only its antioxidant properties were considered.28 Vitamin E has been shown to inhibit different key events in inammation29 and signaling cascades such as inuencing the phosphorylation state of protein kinase C, a key player in the signaling of cytokines,30 which may be relevant to AD. Another antioxidant, vitamin C (ascorbic acid), participates in several enzymatic reactions essential to the synthesis of catecholamines.31 There is considerable evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of AD.32 Various epidemiologic studies have reported that dietary intake of antioxidants vitamins E and C, especially vitamin E, is associated with a lower risk of incident AD. Some studies reported that vitamin C supplement use was related to lower risk of AD;33 however, other studies did not support previous association between combined use of vitamin E and C supplements and lower risk of AD.34 Recently, a series of reports on vitamin E intake and dementia 21,35,36 encouraged investigators conducting current clinical trials to test the effectiveness of vitamin E and other antioxidants in preventing or postponing cognitive decline and AD. These recent publications found a signicant association between vitamin E intake and cognitive decline and dementia. A diet that includes whole-grain cereal for breakfast, a sandwich with whole-grain bread for lunch, and a dinner including a green leafy salad sprinkled with nuts, for example, would contain levels of vitamin E consumed by participants with the highest vitamin E intake in these studies. Engelhart and colleagues, 21 to assess the effects of antioxidants on cognitive function, addressed the role of antioxidants in the context of primary prevention; they suggested that a diet rich in foods containing high amounts of vitamins E and C may help to protect against AD. This study, conducted in the Netherlands, collected data on 5395 men and women, who were at least 55 years of age, who were participants in the population-based Rotterdam Study, and who were free of dementia at baseline.
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After a mean follow-up of 6 years, there were 197 cases of dementia; 146 of these cases were diagnosed as AD. Data were adjusted for age, sex, baseline MiniMental State Examination score, alcohol intake, education, smoking, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and the use of antioxidant supplements. After this adjustment, the researchers found that a high dietary intake of vitamin C and vitamin E was associated with a reduced risk of AD and this relationship was strongest among current smokers (Table1). Persons in the highest tertile of vitamin E intake from food (15.5 mg/day) were 43% less likely to develop AD. These ndings may reect a cumulative benet of antioxidant intake over a long period. The study also reported that vitamin E in the form of supplements was surprisingly not associated with a reduction in the risk of AD. A few years ago, a randomized controlled trial37 of supplemental vitamin E performed in patients with AD suggested that vitamin E at a dose of 1000 IU given twice daily to patients with moderately severe cognitive impairment slowed the progression of the disease and delayed the time to nursing home placement. Vitamin E supplementation in patients with AD delayed important dementia milestones, such as patients institutionalization or progression to severe dementia by approximately 7 months. There is no apparent explanation for this noticeable divergence in the protective effect of vitamin intake from dietary sources as opposed to from supplement use. Studies on supplement use are more prone to bias because people who use supplements may have more health problems and more healthy behaviors.38,39 In addition, various other factors could be important modiers of supplement effects, such as the length of time taking the supplement, constancy, amount, purity and type of preparation, and the composition of the mixture. An important concern of this study is perhaps the potential inuence of the preclinical illness on either diet or supplement use, or on the way the patients reported their intake. For example, a patient who has problems rememTable 1. Effect of Vitamin E on Risk of AD after 6 Years of Follow-up
Association between Antioxidants Intake and Risk of AD (RR) Smokers Nonsmokers

Dietary Intake of:

Vitamin E Vitamin C -carotene Flavonoids

0.58 0.65 0.49 0.54

0.82 0.82 Not reported Not reported

Participants 5395, dementia 197, AD 146. AD Alzheimers disease, RR relative risk.

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bering recent events might not accurately report recent dietary intake and supplement use. Alternatively, a patient who recognized signs of a decline in memory might be more likely to begin taking supplements. Early symptoms of developing dementia might be sufcient reason to precipitate supplement use or an improved diet; on the contrary, the nature of the illness might lead to a reversal of such reasonable behavior as the illness progresses. These uncertainties highlight the great difculty inherent in observational studies that depend on recall of information for estimation of risk factor exposures for illnesses that have a long course, which could cause alterations in brain functions that inuence behaviors, communication, memory, and other cognitive activity. Measurement of blood levels of nutrients can reduce some of the limitations underlying the validity of these studies. Another concern in this study is that enrolled subjects were young, 55 years of age at baseline. The low incidence rates of dementia reported reect the age of the population selected. Incidence rates for dementia are quite low until approximately 60 years; after 65 years rates generally double every 5 to 8 years of increasing age. In this study, nonsmokers were found to obtain no benet from antioxidants. Smoking increases the formation of free radicals and oxidative stress. More than 20% of the subjects enrolled in this cohort were current smokers and analyses were stratied to address a possible interaction of smoking and nutrient intake. The analyses showed a strong association between vitamin E and AD among smokers, but no association among those who never smoked. Various factorsthe predominately lowrisk population enrolled in the study, subjects were 55 years of age, and a relatively short period (6 years) of follow-upmay have contributed to lack of association reported between vitamin E and dementia among those who never smoked. A source of potential bias in this study is the use of a food frequency questionnaire (FFQ) to estimate dietary intake of antioxidants. This methodology requires that the patient recall and report the consumption of a large number of individually specied foods (178 items); the FFQ routinely asks about usual serving sizes and frequency of consumption in specied intervals during a general time period. Therefore, FFQ responses require continuous motivation, attention, and memory. Patients with more preserved functional ability might therefore be expected to provide more accurate FFQ data concerning foods rich in antioxidant nutrients. Declines in attention and memory function that precede AD, but are not yet evident, could also inuence estimates of food intake on the FFQ. Dietary assessment was performed only once and may not precisely reect the participants long-term dietary habits. The study also reported no association of vitamin E intake on AD in
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those individuals with the apolipoprotein E4 allele (APOE) genotype. However, this genotype is a risk factor for late development of AD.40 In addition, subjects with APOE may have a positive family history of AD, and may consequently be diagnosed at a younger age; this would affect the inuence of antioxidants on the development of AD or the preclinical cognitive manifestations of the underlying neurodegenerative process on behavior. These inaccuracies are of potential concern in this type of study because they can introduce systematic measurement error and contribute to residual confounding for which investigators are unable to correct. Despite the potential problems, the ndings reported by this study are important and interesting. The suggestion that antioxidants might have benecial effects on the underlying changes associated with the pathogenesis of AD is very important and supports the promotion of higher dietary intake of antioxidant-rich foods. Welldesigned intervention trials, as well as observational investigations based on larger cohorts, with longer study duration, and using multiple methodologies to assess molecular and antioxidant effects, are necessary to test the hypothesis.
1. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology. 2002;58:1629 1634. Bowler JV, Wade JP, Jones BE, Nijran KS, Steiner TJ. Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT. J Neurol Neurosurg Psychiatry. 1998;64:90 97. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimers disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:13371342. Seshadri S, Wolf PA, Beiser A, et al. Lifetime risk of dementia and Alzheimers disease. The impact of mortality on risk estimates in the Framingham Study. Neurology. 1997;49:1498 1504. Souder E, Chastain JR, Williams RD. Dementia in the new millennium. Medsurg Nurs. 2002;11:61 69, 70. Koppel R. Alzheimers disease: the costs to U.S. businesses in 2002. Prepared for the Alzheimers Association. Philadelphia, PA: Social Research Corporation and Department of Sociology, University of Pennsylvania; 2002:128. Ernst RL, Hay JW. The US economic and social costs of Alzheimers disease revisited. Am J Public Health. 1994;84:12611264. Markesbery WR. Oxidative stress hypothesis in Alzheimers disease. Free Radic Biol Med. 1997;23: 134 147. Andorn AC, Pappolla MA. Catecholamines inhibit lipid peroxidation in young, aged, and Alzheimers disease brain. Free Radic Biol Med. 2001;31:315 320. Behl C. Amyloid beta-protein toxicity and oxidative

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The Relationship between Obesity and Breast Cancer Risk and Mortality
Obesity is an established risk factor for postmenopausal, but not premenopausal, development of breast cancer. Evidence for a positive association between obesity and breast cancer mortality is mounting. Avoiding adult weight gain and maintaining a healthy body weight may contribute importantly to decreasing breast cancer risk and mortality, especially in postmenopausal women. Key Words: obesity, BMI, breast cancer risk, breast cancer mortality
2003 International Life Sciences Institute doi: 10.131/nr.2003.febr.7376

Obesity is an established risk factor for breast cancer in postmenopausal women,1 but not in premenopausal
This review was prepared by Junaidah B. Barnett, Ph.D., MCH(N), Friedman School of Nutrition Science and Policy at Tufts University, and Department of Family Medicine and Community Health, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
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women.2 Few studies have assessed the relationship between obesity and breast cancer mortality. Obesity has been shown to increase breast cancer mortality in women after menopause in the Nurses Health Study by Huang et al.3 and in a large Norwegian study by Tretli.4 The recently published study in Cancer Causes and Control by Petrelli et al.5 strongly supports these ndings. The authors showed that breast cancer mortality rates increased continually and substantially with increasing body mass index (BMI, kg/m2) in postmenopausal women (relative risk [RR] 3.08, 95% condence interval [CI] 2.09 4.51 for BMI 40 compared with BMI 18.520.49 [p for trend 0.0001]). The authors used a sample of 424,168 eligible women who were postmenopausal and cancer-free at baseline. These women were selected from 676,306 female participants in the Cancer Prevention Study II, a prospective mortality study of American men and women begun by the American Cancer Society in 1982. After 14 years of follow-up, 2,852 breast cancer deaths were observed. Cox proportional hazards modeling was used to estimate relative risk and to control for potential confounders such
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